SUMMARY Although most smokers want to stop smoking, few successfully quit long-term. ?7 nicotinic acetylcholine receptors (nAChR) are an important pharmacological target for development of new smoking cessation medications. ?7 nAChRs regulate cognitive processes of attention, learning and memory, as well emotional affect and reward, the same processes that are enhanced by acute nicotine, and disrupted during tobacco withdrawal. Preclinical research provides evidence that ?7 nAChR play a role in the reinforcing effects of nicotine and expression of nicotine withdrawal, and that these receptors are upregulated in key brain regions after chronic nicotine exposure. The proposed proof-of-concept pilot study will first quantify ?7 nAChR in recently abstinent tobacco smokers using human Positron Emission Tomography (PET) with an ?7 nAChR selective radiotracer (18F-ASEM) to determine if ?7 nAChR availability is higher in smokers when compared to healthy control nonsmokers, and if ?7 nAChR availability is correlated with magnitude of tobacco use (Aim1). Ain 2 will also explore the potential relationship of ?7 nAChR availability to clinically relevant measures of tobacco withdrawal during acute abstinence. Non-treatment seeking heavy smokers with TUD will be enrolled into an outpatient protocol that includes 18F-ASEM PET imaging of ?7 nAChR availability after 24-hrs of smoking abstinence. Self-report of tobacco craving, withdrawal discomfort, and negative affect as well as heart rate and performance on a task that measures attention processing will be assessed at baseline when smoking as usual, on the first day of abstinence, then each study visit during the quit attempt. We will use a standard, validated behavioral intervention (contingency management) to motivate smoking abstinence during the 8-day quit attempt; at each study visit participants will receive incentive payments contingent upon criterion levels of exhaled carbon oxide (CO) and urinary cotinine levels indicative of abstinence compliance, and number of days of successful abstinence will be determined. Use of 18F-ASEM is approved by the FDA for human use under an IND. These data provide a critical first step towards understanding ?7 nAChR characteristics in TUD and as a potential pharmacotherapeutic target to promote smoking cessation.